4v12 › Citations

A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis.

Carrère-Kremer S, Blaise M, Singh VK, Alibaud L, Tuaillon E, Halloum I, van de Weerd R, Guérardel Y, Drancourt M, Takiff H, Geurtsen J, Kremer L
Mol Microbiol 96 1085-102 (2015)
Cited: 15 times
EuropePMC logo PMID: 25754266

Abstract

Nontuberculous mycobacteria are innately resistant to most antibiotics, although the mechanisms responsible for their drug resistance remain poorly understood. They are particularly refractory to thiacetazone (TAC), a second-line antitubercular drug. Herein, we identified MSMEG_6754 as essential for the innate resistance of Mycobacterium smegmatis to TAC. Transposon-mediated and targeted disruption of MSMEG_6754 resulted in hypersusceptibility to TAC. Conversely, introduction of MSMEG_6754 into Mycobacterium tuberculosis increased resistance 100-fold. Resolution of the crystal structure of MSMEG_6754 revealed a homodimer in which each monomer comprises two hot-dog domains characteristic of dehydratase-like proteins and very similar to the HadAB complex involved in mycolic acid biosynthesis. Gene inactivation of the essential hadB dehydratase could be achieved in M. smegmatis and M. tuberculosis only when the strains carried an integrated copy of MSMEG_6754, supporting the idea that MSMEG_6754 and HadB share redundant dehydratase activity. Using M. smegmatis-Acanthamoeba co-cultures, we found that intra-amoebal growth of the MSMEG_6754 deleted strain was significantly reduced compared with the parental strain. This in vivo growth defect was fully restored upon complementation with catalytically active MSMEG_6754 or HadABC, indicating that MSMEG_6754 plays a critical role in the survival of M. smegmatis within the environmental host.

Articles - 4v12 mentioned but not cited (1)

  1. Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. Halloum I, Carrère-Kremer S, Blaise M, Viljoen A, Bernut A, Le Moigne V, Vilchèze C, Guérardel Y, Lutfalla G, Herrmann JL, Jacobs WR, Kremer L. Proc. Natl. Acad. Sci. U.S.A. 113 E4228-37 (2016)


Reviews citing this publication (3)

  1. Mycolic acids: deciphering and targeting the Achilles' heel of the tubercle bacillus. Nataraj V, Varela C, Javid A, Singh A, Besra GS, Bhatt A. Mol. Microbiol. 98 7-16 (2015)
  2. NTM drug discovery: status, gaps and the way forward. Wu ML, Aziz DB, Dartois V, Dick T. Drug Discov. Today 23 1502-1519 (2018)
  3. Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities. Egorova A, Jackson M, Gavrilyuk V, Makarov V. Med Res Rev 41 2350-2387 (2021)

Articles citing this publication (11)

  1. The ESX-5 System of Pathogenic Mycobacteria Is Involved In Capsule Integrity and Virulence through Its Substrate PPE10. Ates LS, van der Woude AD, Bestebroer J, van Stempvoort G, Musters RJ, Garcia-Vallejo JJ, Picavet DI, Weerd Rv, Maletta M, Kuijl CP, van der Wel NN, Bitter W. PLoS Pathog. 12 e1005696 (2016)
  2. Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384. Halloum I, Viljoen A, Khanna V, Craig D, Bouchier C, Brosch R, Coxon G, Kremer L. Antimicrob. Agents Chemother. 61 (2017)
  3. A unique PE_PGRS protein inhibiting host cell cytosolic defenses and sustaining full virulence of Mycobacterium marinum in multiple hosts. Singh VK, Berry L, Bernut A, Singh S, Carrère-Kremer S, Viljoen A, Alibaud L, Majlessi L, Brosch R, Chaturvedi V, Geurtsen J, Drancourt M, Kremer L. Cell. Microbiol. 18 1489-1507 (2016)
  4. iniBAC induction Is Vitamin B12- and MutAB-dependent in Mycobacterium marinum. Boot M, Sparrius M, Jim KK, Commandeur S, Speer A, van de Weerd R, Bitter W. J. Biol. Chem. 291 19800-19812 (2016)
  5. Cell envelope stress in mycobacteria is regulated by the novel signal transduction ATPase IniR in response to trehalose. Boot M, van Winden VJC, Sparrius M, van de Weerd R, Speer A, Ummels R, Rustad T, Sherman DR, Bitter W. PLoS Genet. 13 e1007131 (2017)
  6. Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria. Tsai YT, Salzman V, Cabruja M, Gago G, Gramajo H. Open Biol 7 (2017)
  7. The Non-Essential Mycolic Acid Biosynthesis Genes hadA and hadC Contribute to the Physiology and Fitness of Mycobacterium smegmatis. Jamet S, Slama N, Domingues J, Laval F, Texier P, Eynard N, Quémard A, Peixoto A, Lemassu A, Daffé M, Cam K. PLoS ONE 10 e0145883 (2015)
  8. The endogenous galactofuranosidase GlfH1 hydrolyzes mycobacterial arabinogalactan. Shen L, Viljoen A, Villaume S, Joe M, Halloum I, Chêne L, Méry A, Fabre E, Takegawa K, Lowary TL, Vincent SP, Kremer L, Guérardel Y, Mariller C. J Biol Chem 295 5110-5123 (2020)
  9. A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis. Farjallah A, Chiarelli LR, Forbak M, Degiacomi G, Danel M, Goncalves F, Carayon C, Seguin C, Fumagalli M, Záhorszká M, Vega E, Abid S, Grzegorzewicz A, Jackson M, Peixoto A, Korduláková J, Pasca MR, Lherbet C, Chassaing S. ACS Infect Dis 7 552-565 (2021)
  10. Deletion of MSMEG_1350 in Mycobacterium smegmatis causes loss of epoxy-mycolic acids, fitness alteration at low temperature and resistance to a set of mycobacteriophages. Di Capua CB, Belardinelli JM, Buchieri MV, Bortolotti A, Franceschelli JJ, Morbidoni HR. Microbiology (Reading, Engl.) 164 1567-1582 (2018)
  11. Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives. Madacki J, Kopál M, Jackson M, Korduláková J. Int J Mol Sci 22 2884 (2021)


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